The percutaneous penetration of chemicals accounts for a significant number of toxic observations. The ability to predict and hence minimize exposure and toxic potential is routinely based upon acute exposure and a single dose transdermal absorption determination. However, the more environmentally and occupationally relevant situation often involves multiple cutaneous exposure for which very little experimental investigation has been performed. The objectives of this project are (1) to initiate chronic percutaneous absorption studies in an animal model, and (2) to develop and validate a new pharmacokinetic simulation for interpretation and prediction of transdermal penetration kinetics following multiple skin application. Absorption experiments will be performed in the rhesus monkey. Penetrants to be studied will include chemicals chosen to test the proposed simulation through their diverse absorption characteristics (e.g. benzoic acid, caffeine, testosterone) and toxicologically important substances such as malathion, paraquat and benzene. Daily application will be made for 2-3 weeks and absorption assessed by monitoring the plasma level or urinary excretion rate of periodic radiolabelled doses (e.g. labelled chemical applied on days 1, 5, 9; cold material on all other days). A new kinetic model, based on distinct physical processes involved in skin penetration, will interpret the data. Rate constants will be found which measure a penetrant's lifetime at various regions within the skin and which control, therefore, the levels of chemical attained both in the barrier and systemically. In the long-term, this project strives (a) to determine situations in which acute "single-shot" percutaneous penetration assessments are either useful or deficient for indicating potential toxicity after multiple exposure, and (b) to provide a sound biophysical simulation for transdermal pharmacokinetics that has the ability to prevent the time course of skin and systemic disposition following repeated topical applications of penetrant.